This invention is in the area of controlled delivery systems for substances, including pharmaceuticals.
Many dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds. These systems are designed to protect the substance from the environment during delivery and to provide a controlled release of the substance to a targeted area. In some cases, the goal is to target specific sites in the body using the dispersion. In other cases, the goal is to prepare a drug carrier system that acts as a reservoir at the site of injection. Dispersed systems for delivery are also important in the non-pharmaceutical area, for example, for use in the controlled release of substances such as insecticides, fungicides, herbicides and pheromones.
Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions. Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in an aqueous or nonaqueous medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.
Emulsions can be defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Despite their long history, emulsions are used less often today than many other dosage forms due to the inherent instability. Emulsion formulations include water in oil and oil in water emulsions, multiple water/oil/water emulsions, microemulsions, microdroplets, and liposomes.
Microdroplets are unilamellar phospholipid vesicles that consist of a spherical lipid layer with an oil phase inside, as defined in Haynes U.S. Pat. No(s). 4,622,219 and 4,725,442. These phospholipid coated microdroplets of hydrophobic liquid drugs, or drugs dissolved in an organic solvent, can be used as a means to deliver a water insoluble general anesthetic to a local region of the body.
Liposomes are phospholipid vesicles prepared by mixing water-insoluble polar lipids with excess water or an aqueous solution. The unfavorable entropy caused by mixing the insoluble lipid in the water produces a highly ordered assembly of concentric closed membranes of phospholipid with entrapped aqueous solution. The membrane consists of a bimolecular sheet of lipid molecules that have their hydrophobic centers aligned in the middle of the membrane, and hydrophilic ends on the outside of the membrane, interfacing with the aqueous solution, and on the inside, interfacing with entrapped aqueous solution. A unilamellar liposome has a single membrane encapsulating a solution. A multilamellar liposome has a series of membranes, each of which is separated from the neighboring membrane by water. Unilamellar liposomes have a minimum size of about 25 nanometers in diameter, while multilamellar liposomes can range up to several micrometers. The rigidity and permeability of phospholipid bilayers can be adjusted by including other water-insoluble components such as sterols and amphiphiles with the phospholipid.
As noted above, while emulsion based delivery systems are useful for certain applications, the delivering vesicles are subject to physical rupture because of the delicate nature of the liquid/membrane/liquid structure. Emulsion based delivery systems also have relatively short release times. Further, it is difficult to isolate emulsion based vesicles from the aqueous media used for storage for subsequent reconstitution.
The solid phase vesicles in suspension based delivery systems are more stable than the liquid vesicles in emulsion based delivery systems. However, in suspension based systems the concentration of the suspension and the interaction between the vesicles and the liquid carrier is limited because of the repulsive interaction between the solid and the carrier.
It is therefore an object of the present invention to provide a controlled delivery system for substances that is stable for an extended time.
It is another object of the present invention to provide a controlled delivery device that has a relatively long release time.
It is still another object of this invention to provide a suspension delivery vesicle that can be isolated for storage and then resuspended when desired.